Inhibition of apoptosis by 60% oxygen: a novel pathway contributing to lung injury in neonatal rats

Abstract

During early postnatal alveolar formation, the lung tissue of rat pups undergoes a physiological remodeling involving apoptosis of distal lung cells. Exposure of neonatal rats to severe hyperoxia (≥95% O(2)) both arrests lung growth and results in increased lung cell apoptosis. In contrast, exposure to moderate hyperoxia (60% O(2)) for 14 days does not completely arrest lung cell proliferation and is associated with parenchymal thickening. On the basis of similarities in lung architecture observed following either exposure to 60% O(2), or pharmacological inhibition of physiological apoptosis, we hypothesized that exposure to 60% O(2) would result in an inhibition of physiological lung cell apoptosis. Consistent with this hypothesis, we observed that the parenchymal thickening induced by exposure to 60% O(2) was associated with decreased numbers of apoptotic cells, increased expressions of the antiapoptotic regulator Bcl-xL, and the putative antiapoptotic protein survivin, and decreased expressions of the proapoptotic cleaved caspases-3 and -7. In summary, exposure of the neonatal rat lung to moderate hyperoxia results in an inhibition of physiological apoptosis, which contributes to the parenchymal thickening observed in the resultant lung injury.

Severity of neonatal hyperoxia determines structural and functional changes in developing mouse airway

“…Furthermore, we have shown that levels of supplemental oxygen Ͼ60% cause apoptosis in human fetal ASM cells in contrast to the ASM proliferation observed at lower levels of oxygen exposure (6). This is consistent with the inhibition of apoptosis observed in lung cells of neonatal rats exposed to 60% compared with 95% oxygen (23). We therefore sought to test the hypothesis that modest hyperoxic exposure would cause a greater increase in airway reactivity compared with severe hyperoxia and that this response would be sustained beyond completion of hyperoxic exposure.…”

“…Prior studies have reported on the role of 95-100% hyperoxic exposure in promoting apoptosis in the mesenchyme of the developing lung (4). In contrast, more recent data have proposed that 60% oxygen exposure for 14 days may inhibit apoptosis and contribute to parenchymal thickening in neonatal rat lungs (23). In a prior study we sought to determine the role of various oxygen concentrations in inducing proliferation of human fetal ASM cells under in vitro conditions (6).…”

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…Patients with ARDS generally require positive-pressure ventilation with high fractions of inspired oxygen causing hyperoxia in the lung. Hyperoxia may also contribute to lung injury primarily by initiating ROS generation (8,117) and activating the inflammasome (122), leading to altered mechanical properties (198) and apoptosis (23,144,148,263) of alveolar epithelial cells. As a consequence of protective ventilation with low tidal volumes, a number of patients display elevated levels of CO 2 , termed permissive hypercapnia.…”

Chronic lung injury in the neonatal rat: Up-regulation of TGFβ1 and nitration of IGF-R1 by peroxynitrite as likely contributors to impaired alveologenesis

“…Pathogen-free timed-pregnant Sprague-Dawley rats (250-275 g) were obtained from Charles River (St-Constant, Senneville, QC, Canada). Rat pups (10-12/litter) were exposed to air or 60% O 2 in paired chambers (Biospherix, Lacona, NY, USA) for up to 14 days, as previously described [9,[12][13][14][15][16][17][18][19]. Pups were delivered inside the chambers.…”

“…Neonatal rats exposed to 60% O 2 from birth for 14 days develop a chronic neonatal lung injury with many of the pathological features observed in human BPD. These include impaired alveologenesis, Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/freeradbiomed parenchymal thickening, and evidence of pulmonary hypertension with small vessel pruning [8][9][10][12][13][14][15][16][17][18][19][20]. Marked immunoreactivity of lung tissue for nitrotyrosine is evident following exposure to 60% O 2 [13], which is prevented by concurrent treatment with a peroxynitrite decomposition catalyst [18].…”